For Bristol-Myers, A Victory And A Mystery

New data presented at a medical conference show that combining Bristol-Myers Squibb’s two immune-boosting cancer drug appears to extend the lives of melanoma patients longer than using either alone.

But a big question lingers about one of the drugs, Opdivo: why did it fail to extend survival in patients with previously untreated non-small cell lung cancer, when a very similar drug from Merck proved effective? A trial being presentd this afternoon may yield some clues. Both studies are being presented at the annual meeting of the American Association for Cancer Research.

“I think that’s obviously been the topic of debate for the last seven or eight months,” says Naiyer Rizvi, director of thoracic oncology at New York-Presbyterian/Columbia University Medical Center, of the lung cancer failure. “I don’t thnk anyone has an answer.”

Billions of dollars are at stake. Last year, Bristol sold $3.6 billion worth of Opdivo globally, compared to $1.4 billion of Merck’s Keytruda. But because of the discordant lung cancer results, financial analysts at J.P. Morgan forecast that next year, the Merck drug will take the lead, with $6 billion in annual sales, compared to $4.8 billion in sales for Opdivo. Bristol shares are down 18% over the past 12 months as a result of the lung cancer result, while Merck shares are up 17%.

The melanoma results will be welcome news against that backdrop. The 945-patient study compared Opdivo alone, an older Bristol melanoma drug called Yervoy, and the combination of the two. Researchers already revealed that the Opdivo slowed tumor growth more than Yervoy, and that the combination slowed tumors more than either alone.

But skeptics worried that wouldn’t translate into longer lives for patients, particularly since once patients’ tumors grew, they were allowed to switch to the Opdivo-Yervoy combination. Extending patients’ lives in the control group could make the trial look less positive. The concern was heightened because the combination was approved by the Food and Drug Administration on an accelerated basis, which means the approval could have been withdrawn if the results disappointed.

The worries were unfounded. The median survival for patients on Yervoy was 28 months; a median had not been reached for Opdivo alone or the combo. At two years, 64% of those on the Opdivo-Yervoy combo were alive, compared to 59% of those on Opdivo alone and 45% of those on Yervoy. Both the combination and Opdivo were significantly better than Yervoy alone. The difference between Opdivo alone and the combination was not statistically significant.

The data are being presented here in Washington, D.C., at the annual meeting of the American Association for Cancer Research.

Fouad Namouni, who heads studies of the drugs at Bristol, called the result “a major advance.”

Serious side effects were more common with the drug combo than with either drug alone. Financial cost is also an issue: the combination has a list price of a quarter of a million dollars.

Given the positive results in skin cancer, and also in lung cancers that have not been helped by other treatments, why didn’t Bristol succeed in previously untreated lung cancer patients, the biggest market for these immune-boosting cancer drugs?

Researchers have been scratching their heads asking that question. Most are fairly certain that the answer is not that Opdivo is that different from Merck’s Keytruda. More likely, it has to do with differences in how the studies were designed. One difference, Rizvi posits, could be in the diagnostic tests that Bristol and Merck used to determine if patients’ tumors had high levels of a protein, called PD-L1, that predicts a better response to these drugs.

Another possibility is that the group that got Opdivo wasn’t as similar to the control group that received chemotherapy as it should have been. Another predictor of whether Opdivo and Keytruda are effective may be how many mutations have built up in the cancers they are attacking, a measure called tumor burden. Only 29.7% patients had a high tumor burden in the Opdivo arm of the failed study, compared to 39% in the chemotherapy arm, according to an abstract released at the meeting. Full results are scheduled to be presented at 5:20 pm ET this evening, and Wall Street analysts, researchers, and drug company execs will all be watching for clues of what exactly went wrong in Bristol’s trial.